The objective of this proposal is to understand the causes of synaptic damage that is present in Alzheimer's disease (AD). Increasing evidence indicate that synapse loss is one of the earliest alterations and the best correlate of the cognitive deficits in AD. Consequently, it is crucial to understand what causes synaptic injury in AD, especially in the earliest or even pre-disease stages. Amyloid beta-protein, the major constituent of senile plaques in brain, has been shown to impair synaptic function both in vitro and in vivo. However, the mechanisms by which Abeta induce synaptic dysfunction and synapse loss are not clear. In this project, we will test several hypotheses of Abeta-induced synaptic damage in several animal models of AD-related pathology that share conceptual and technical approaches in common with the other three Projects of this Program. In the first Aim, we will determine whether Abeta released from the pre- or postsynaptic neuron is more important in Abeta induced synaptic dysfunction. This will be tested by selectively expressing amyloid precursor protein (APP) in CA1 or CAS neurons, respectively, and assessing the function of the synapses between these two sets of neurons. The second Aim will examine how age influences Abeta induced synaptic dysfunction in hippocampal neurons. While most studies have concentrated on the effects of Abeta reduction in brain, our approach tests the opposite scenario: how long does Abeta exposure have to be sustained in brain before synaptic transmission is perturbed and whether this is related .toage. Lastly, if synaptic perturbations are indeed early and key contributors to neurodegeneration, then axons are likely to degenerate concomitantly. In this regard, axonal pathology is seen in brains of AD individuals and in animal models. The third Aim will examine the phenotype of APP transgenic mice crossed to the WLDs (slow Wallerian degeneration) mutant mice. Axons in the latter mutant animals are protected in injury and from various toxic agents and neurodegeneration. Consequently, we can test whether preserving axons can attenuate synaptic damage in APP transgenic mice.